1. Field of the Invention
This invention relates to novel substituted imidazolinone derivatives. The invention also relates to pharmaceutical compositions containing the novel imidazolinone derivatives and pharmaceutical methods using them, alone and in conjugation with other drugs.
The compounds of this invention inhibit the action of the hormone angiotensin II(AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma .alpha.2-globulin, angiotensinogen, to produce angiotensin I, which is then converted by ACE to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causative agent for producing high blood pressure in various mammalian species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of this invention are also useful for the treatment of congestive heart failure. Administration of a compound of this invention with a diuretic such as furosemide or hydrochlorothiazide, either as a stepwise combined therapy (diuretic first) or as a physical mixture, enhances the antihypertensive effect of the compound. Administration of a compound of this invention with a NSAID can prevent renal failure which sometimes results from administration of a NSAlD.
Several peptide analogs of All are known to inhibit the effects of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by the partial agonist activity and lack of oral absorption (M. Antonaccio, Clin. Exp. Hypertens., 1982, A4, 27-46; D. H. P. Streeten and G. H. Anderson, Jr., Handbook of Hypertension. Clinical Pharmacology of Antihypertensive Drugs, ed., A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984).
Several non-peptide antagonists of AII have been disclosed. These compounds are covered by U.S. Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804; in European Patent Applications 028,834; 245,637; 253,310; and 291,969; and in articles by A. T. Chiu et at. (Eur. J. Pharm. Exp. Therap., 1988, 157, 13-21) and by P. C. Wong et at. (J. Pharm. Exp. Therap., 1988, 247, 1-7). All of the U.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2H-imidazo 4,5-c!pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents, specifically Ca.sup.2+ channel blockers.
L. Chang et al., in EP 0 412 594 A (filed Jul. 23, 1990) disclose substituted triazolinones, triazolinethiones, and triazolinimines of the formula: ##STR2## These are claimed to be antagonists of AII which are useful for treating hypertension, congestive heart failure (CHF), and elevated intraocular pressure.
C. Bernhart et al., in WO 91/14679 (published Oct. 3, 1991 )disclose heterocyclic N-substituted derivatives of the formula ##STR3## These compounds are disclosed to be antagonists of AII which are useful for treating cardiovascular disorders such as hypertension.
F. Ostermeyer et al., in EP 475,898 (published Mar. 18, 1992) disclose heterocyclic N-substituted derivatives of formula ##STR4## These compounds are disclosed to be antagonists of AII which are useful for treating cardiovascular disorders such as hypertension.
Wagner et al., in EP 0 503 162 (published Sep. 16, 1992) disclose azole derivatives of the general Formula (A) and the specific compound Example 150. ##STR5## These compounds are disclosed to be antagonists of AII which are useful for treating cardiovascular disorders such as hypertension.
P. Herold and P. Buhlmayer in EP 0 407 342 A2 disclose substituted pyrimidinones, pyrimidinethiones, and pyrimidinimines of the formula: ##STR6## These are claimed to be antagonists of AII which are useful for treating hypertension.
E. Allen et al. in EP 0 419 048 A (filed Aug. 21, 1990) disclose a similar series of pyrimidinones which are claimed to be antagonists of All useful for the treatment of CHF and elevated intraocular pressure.